The molecular mechanisms underlying neurodegeneration by apoptosis in Alzheimer's disease (AD) remain enigmatic. Since AD is a chronic condition and current treatments only delay progression of the disease, it is crucial that mechanisms underlying neuronal cell death in AD be elucidated for future therapeutic development. Many cases of familial AD are caused by mutations in presenilin 1 (PS1), but how altered activity of PS1 contributes to the pathogenesis of AD is unclear. The C. elegans homologue of PS1, SEL-12, interacts functionally and physically with the product of the recently identified cps-4 gene (ced-3 cell death protease suppressor), which encodes the homologue of human ubiquilin 1 (UBQLN1). Preliminary studies suggests that cps-4 acts downstream of the CED-3 cell death protease to promote apoptosis, but upstream of or in parallel to sel-12, a cell-death inhibitor gene. The proposed research will characterize the mechanism by which cps-4 interacts with sel-12 to induce apoptosis downstream of ced-3. The following specific aims are to: (1) investigate if the SEL-12-interacting domains of CPS-4 are important for the pro-apoptotic activity of the cps-4 gene;(2) test if cps-4 regulates sel-12-dependent calcium release from the endoplasmic reticulum during apoptosis;and (3) examine the possibility that CPS-4 or SEL-12 is a substrate of the activated CED-3 protease. The proposed research will begin to reveal the molecular mechanisms underlying the conserved interactions among CED-3/caspases, CPS-4/UBQLN1, and SEL-12/PS1. Ultimately, this work will contribute to the understanding of presenilin-dependent neurodegeneration in AD. PUBLIC HEALTH RELEVANCE: Neurodegeneration in Alzheimer's disease (AD) is characterized in part by premature or inappropriate death of brain cells. This research will reveal a connection between genes that promote cell death and presenilin, which is the gene mutated in many cases of familial AD. Understanding this link will facilitate the development of targeted therapies to ameliorate this disease. )